Journal of Alzheimer's Disease - Volume 75, issue 3

Authors: Pyun, Jung-Min | Kang, Min Ju | Ryoo, Nayoung | Suh, Jeewon | Youn, Young Chul | Park, Young Ho | Kim, SangYun

Article Type: Review Article

Abstract: Amyloid-β (Aβ) is a key protein in Alzheimer’s disease (AD) in that its accumulation induces complex pathological changes. Although there has been extensive research on the metabolism of Aβ in AD, new compelling results have recently emerged. Historically, the production and clearance of Aβ have been thought to originate in the central nervous system (CNS). However, recent evidence suggests that the production and clearance of Aβ can also occur in the peripheral system, and that the peripherally driven Aβ migrates to the CNS and induces amyloidopathy with subsequent AD pathologic changes in the brain. This concept implies that AD is …not restricted to the CNS but is a systemic disease instead. As such, the development of blood-based biomarkers targeting Aβ is of great interest. Central and peripheral Aβ are both active contributors to the pathology of AD and interact bidirectionally. Measuring peripheral Aβ is not just observing the reflection of the residual Aβ removed from the CNS but also tracking the ongoing process of AD pathology. Additionally, blood-based biomarkers could be a more accessible tool in clinical and research settings. Through arduous research, several blood-based biomarker assays have demonstrated notable results. In this review, we describe the metabolism of Aβ and the amyloid-targeting blood-based biomarkers of AD. Show more

Keywords: Alzheimer’s disease, amyloid-targeting, amyloid metabolism, blood-based biomarkers

DOI: 10.3233/JAD-200104

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 685-696, 2020

Authors: Kvello-Alme, Marte | Bråthen, Geir | White, Linda R. | Sando, Sigrid Botne

Article Type: Research Article

Abstract: Background: The epidemiology of young onset dementia is little researched compared to late onset dementia. Information on incidence rates is vital for medical professionals, and for government planning purposes. Objective: To determine the incidence of young onset dementia in a defined catchment area of central Norway. Methods: The target area was Trøndelag county in central Norway with a total population of 449,796 inhabitants per January 1, 2016. We applied multiple case ascertainment strategies with sources from both primary and secondary healthcare facilities. Included patients received a diagnosis of dementia according to DSM-IV in the ages 30 …to 64 years during the years 2015–2017. Subtypes of dementia were diagnosed according to standardized criteria. Incidence rates for dementia and Alzheimer’s disease with dementia were calculated according to age and sex. Results: A total of 89 incident cases were included. Incidence rates for dementia were 14.8 and 25.0 per 100,000 person-years for the age range 30–64 and 45–64, respectively. Corresponding incidence rates for Alzheimer’s disease were 6.7 and 11.8. Alzheimer’s disease represented half of all dementias. A majority of patients above the age of 50 had neurodegenerative disease, whereas non-degenerative disorders were more prevalent in younger patients. Conclusion: Young onset dementia is a significant contributor to the overall occurrence of dementia in central Norway, and Alzheimer’s disease is by far the most common diagnosis. Show more

Keywords: Alzheimer’s disease, early onset dementia, epidemiology, frequency, incidence, occurrence, young onset dementia

DOI: 10.3233/JAD-191307

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 697-704, 2020

Authors: Wang, Mei-Ling | Wang, Chong | Tuo, Miao | Yu, Yang | Wang, Lin | Yu, Jin-Tai | Tan, Lan | Chi, Song

Article Type: Research Article

Abstract: Background: Obstructive sleep apnea (OSA) is associated with cognitive impairment and increased risks of dementia. However, the effect of continuous positive airway pressure (CPAP) on cognitive function in patients with OSA is still controversial. Objective: To evaluate the cognitive effects of CPAP treatment on OSA. Methods: We systematically searched PubMed, EMBASE, and Cochrane Library for randomized controlled trials (RCT) in the corresponding fields. Results: Totally 14 studies and 1,926 participants were included in our meta-analysis. Standardized mean difference (SMD) or weighted mean difference (WMD) were calculated for subjective sleepiness and cognitive domains including attention …and speed of information processing, executive function, and memory. Individual cognitive scale and subgroup analyses according to OSA severity, length of trial, and RCT design type were further conducted. Significant treatment effect on attention and speed of information processing was only observed in severe OSA patients (SMD, 0.17; 95% CI, 0.02 to 0.31; p  = 0.025; I2  = 0%). Conclusions: Therefore, our meta-analysis indicates that CPAP treatment can partially improve cognitive impairment in the population of severe OSA. Show more

Keywords: Cognition, continuous positive airway pressure, meta-analysis, obstructive sleep apnea

DOI: 10.3233/JAD-200088

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 705-715, 2020

Authors: Aschwanden, Damaris | Aichele, Stephen | Ghisletta, Paolo | Terracciano, Antonio | Kliegel, Matthias | Sutin, Angelina R. | Brown, Justin | Allemand, Mathias

Article Type: Research Article

Abstract: Background: Efforts to identify important risk factors for cognitive impairment and dementia have to date mostly relied on meta-analytic strategies. A comprehensive empirical evaluation of these risk factors within a single study is currently lacking. Objective: We used a combined methodology of machine learning and semi-parametric survival analysis to estimate the relative importance of 52 predictors in forecasting cognitive impairment and dementia in a large, population-representative sample of older adults. Methods: Participants from the Health and Retirement Study (N = 9,979; aged 50–98 years) were followed for up to 10 years (M  = 6.85 for cognitive impairment; M  = 7.67 …for dementia). Using a split-sample methodology, we first estimated the relative importance of predictors using machine learning (random forest survival analysis), and we then used semi-parametric survival analysis (Cox proportional hazards) to estimate effect sizes for the most important variables. Results: African Americans and individuals who scored high on emotional distress were at relatively highest risk for developing cognitive impairment and dementia. Sociodemographic (lower education, Hispanic ethnicity) and health variables (worse subjective health, increasing BMI) were comparatively strong predictors for cognitive impairment. Cardiovascular factors (e.g., smoking, physical inactivity) and polygenic scores (with and without APOE ɛ 4) appeared less important than expected. Post-hoc sensitivity analyses underscored the robustness of these results. Conclusions: Higher-order factors (e.g., emotional distress, subjective health), which reflect complex interactions between various aspects of an individual, were more important than narrowly defined factors (e.g., clinical and behavioral indicators) when evaluated concurrently to predict cognitive impairment and dementia. Show more

Keywords: Aging, cognitive impairment, Cox proportional hazard survival analysis, dementia, machine learning, protective factors, random forest survival analysis, risk factors

DOI: 10.3233/JAD-190967

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 717-728, 2020

Authors: Sun, Yan | Tan, Lin | Xu, Wei | Wang, Zuo-Teng | Hu, Hao | Li, Jie-Qiong | Dong, Qiang | Tan, Lan | Yu, Jin-Tai | on behalf of Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: White matter hyperintensities (WMH) is mainly caused by cerebrovascular injury and may also increase the possibilities of progression to Alzheimer’s disease. The present study aims to determine whether plasma neurofilament light (NFL) protein levels could predict the progression of WMH volume in elderly persons without dementia. The present study enrolled 1029 non-dementia participants from the Alzheimer’s Disease Neuroimaging Initiative in which all had measurements of plasma NFL and WMH at baseline and 589 had longitudinal measurements during follow-up. Spearman correlation analyses and regression models were used to assess cross-sectional and longitudinal associations between plasma NFL and WMH. Plasma NFL concentration …had a moderately strong correlation with WMH at baseline (r = 0.17, p  < 0.001). Longitudinal analyses showed that higher baseline plasma NFL concentration was associated with accelerated progression of WMH (β=0.015, p  = 0.007). Furthermore, higher change rates of plasma NFL could predict faster progression of WMH in the future (β=0.581, p  = 0.002). The results of the study suggest that plasma NFL level might be used as a noninvasive biomarker to track variation trend in WMH in elderly persons without dementia. Show more

Keywords: Alzheimer’s disease neuroimaging initiative, cognitively decline, non-dementia elders, noninvasive biomarker, plasma neurofilament light protein, white matter hyperintensity

DOI: 10.3233/JAD-200022

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 729-737, 2020

Authors: Petersen, Melissa | Hall, James | Parsons, Thomas | Johnson, Leigh | O’Bryant, Sid

Article Type: Research Article

Abstract: Background: Recent work has supported use of blood-based biomarkers in detection of amnestic mild cognitive impairment (MCI). Inclusion of neuropsychological measures has shown promise in enhancing utility of biomarkers to detect disease. Objective: The present study sought to develop cognitive-biomarker profiles for detection of MCI. Methods: Data were analyzed on 463 participants (normal control n  = 378; MCI n  = 85) from HABLE. Random forest analyses determined proteomic profile of MCI. Separate linear regression analyses determined variance accounted for by select biomarkers per neuropsychological measure. When neuropsychological measure with the least shared variance was identified, it was then …combined with select biomarkers to create a biomarker-cognitive profile. Results: The biomarker-cognitive profile was 90% accurate in detecting MCI. Among amnestic MCI cases, the detection accuracy of the biomarker-cognitive profile was 92% and increased to 94% with demographic variables. Conclusion: The biomarker-cognitive profile for MCI was highly accurate in its detection with use of only five biomarkers. Show more

Keywords: Blood based, biomarkers, mexican american, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-191264

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 739-750, 2020

Authors: Kaipainen, Aku | Jääskeläinen, Olli | Liu, Yawu | Haapalinna, Fanni | Nykänen, Niko | Vanninen, Ritva | Koivisto, Anne M. | Julkunen, Valtteri | Remes, Anne M. | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers of neurodegenerative diseases are relatively sensitive and specific in highly curated research cohorts, but proper validation for clinical use is mostly missing. Objective: We studied these biomarkers in a novel memory clinic cohort with a variety of different neurodegenerative diseases. Methods: This study consisted of 191 patients with subjective or objective cognitive impairment who underwent neurological, CSF biomarker (Aβ42 , p-tau, and tau) and T1-weighted MRI examinations at Kuopio University Hospital. We assessed CSF and imaging biomarkers, including structural MRI focused on volumetric and cortical thickness …analyses, across groups stratified based on different clinical diagnoses, including Alzheimer’s disease (AD), frontotemporal dementia, dementia with Lewy bodies, Parkinson’s disease, vascular dementia, and mild cognitive impairment (MCI), and subjects with no evidence of neurodegenerative disease underlying the cognitive symptoms. Imaging biomarkers were also studied by profiling subjects according to the novel amyloid, tau, and, neurodegeneration (AT(N)) classification. Results: Numerous imaging variables differed by clinical diagnosis, including hippocampal, amygdalar and inferior lateral ventricular volumes and entorhinal, lingual, inferior parietal and isthmus cingulate cortical thicknesses, at a false discovery rate (FDR)-corrected threshold for significance (analysis of covariance; p  < 0.005). In volumetric comparisons by AT(N) profile, hippocampal volume significantly differed (p  < 0.001) between patients with normal AD biomarkers and patients with amyloid pathology. Conclusion: Our analysis suggests that CSF and MRI biomarkers function well also in clinical practice across multiple clinical diagnostic groups in addition to AD, MCI, and cognitively normal groups. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, diagnostic imaging, magnetic resonance imaging, neurodegenerative diseases, tau proteins

DOI: 10.3233/JAD-200175

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 751-765, 2020

Authors: Lee, Seung Hoon | Byun, Min Soo | Lee, Jun Ho | Yi, Dahyun | Sohn, Bo Kyung | Lee, Jun-Young | Kim, Yu Kyeong | Shin, Seong A. | Sohn, Chul-Ho | Lee, Dong Young | for the KBASE ResearchGroup

Article Type: Research Article

Abstract: Background: Although recent studies indicate that the relationship between body mass index (BMI) and Alzheimer’s disease (AD) may differ by both sex and age of BMI measurement, little information is available on sex- or age-specific associations between BMI and AD neuropathologies. Objective: To examined whether sex-specific BMIs measured at different life-stages (in early adulthood, midlife, and late life) were associated with cerebral amyloid-β (Aβ) deposition and AD-signature region cortical thickness (AD-CT) in cognitively normal (CN) older adults. Methods: A total of 212 CN subjects aged 60–90 years (females 108, males 104), who participated in the Korean …Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessments, [11 C] Pittsburgh Compound B positron emission tomography, and brain magnetic resonance imaging. BMIs at different life stages were calculated. Multiple regression analyses were performed separately for either sex. Results: In males, lower early adulthood or midlife BMI was associated with greater cerebral Aβ deposition, but late life BMI was not. Lower midlife BMI was associated with reduced AD-CT, but the BMI in early adulthood and late life was not. In females, no significant association was observed between any lifetime BMI and Aβ deposition or AD-CT. Conclusion: Our results support a male-specific association between BMI prior to late life, and in vivo AD pathologies. Avoiding underweight status early in life may be important to prevent AD dementia in males, but not females. Show more

Keywords: Alzheimer’s disease, cerebral amyloid, lifetime body mass index, neurodegeneration, sex

DOI: 10.3233/JAD-191216

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 767-777, 2020

Authors: Xing, Yi | Zhu, Zude | Du, Yifeng | Zhang, Junjian | Qu, Qiumin | Sun, Li | Li, Yang | Guo, Yanjun | Peng, Guoping | Liu, Yong | Yu, Yueyi | Qiao, Yuchen | Xie, Beijia | Shi, Xinrui | Lu, Jie | Jia, Jianping | Tang, Yi

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is often the prodromal stage of Alzheimer’s disease (AD). Although previous studies have suggested that computerized cognitive training is an effective non-pharmacological intervention for aMCI, large-sample, randomized controlled studies are warranted to provide a high level of evidence. Objective: To identify the efficacy of computerized cognitive training for aMCI. Methods: This study will include 260 patients diagnosed with aMCI from 8 centers in China. A computerized multi-domain adaptive training program will be used in this study, and the targeted cognitive domains include memory, attention, language, and executive function. The patients …will be randomized into either a cognitive-training group or an active-control group. The intervention is a 12-week internet-based cognitive training performed for 40 minutes per day, 4 days a week. Neuropsychological assessments and structural and functional MRI will be obtained at baseline, at the end of the intervention, and 6 months after randomization. The primary outcome will be the global cognitive function score assessed by Montreal Cognitive Assessment. The secondary outcomes include changes in other neuropsychological assessments and neuroplasticity changes measured by structural and functional MRI. Results: The trial is currently ongoing, and it is anticipated that recruitment will be completed in December 2020. Conclusion: This multi-center, large-sample, randomized controlled trial will investigate the short and long-term effects of computerized cognitive training in patients with aMCI. Furthermore, the combination of functional and structural MRI results will also reveal the underlying mechanisms of the effect of intervention. Show more

Keywords: ClinicalTrials.gov NCT04063956, Cognitive training, mild cognitive impairment, non-pharmacological intervention, randomized controlled clinical trial

DOI: 10.3233/JAD-191314

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 779-787, 2020

Authors: Innes, Kim E. | Sambamoorthi, Usha

Article Type: Research Article

Abstract: Background: Emerging evidence suggests osteoarthritis (OA) and related symptom burden may increase risk for Alzheimer’s disease and related dementias (ADRD). However, longitudinal studies are sparse, and none have examined the potential mediating effects of mood or sleep disorders. Objective: To determine the association of OA and related pain to incident ADRD in U.S. elders. Methods: In this retrospective cohort study, we used baseline and two-year follow-up data from linked Medicare claims and Medicare Current Beneficiary Survey files (11 pooled cohorts, 2001–2013). The study sample comprised 16,934 community-dwelling adults≥65 years, ADRD-free at baseline and enrolled in fee-for-service …Medicare. Logistic regression was used to assess the association of OA and related pain (back, neck, joint, neuropathic) to incident ADRD, explore the mediating inlfuence of mood and insomnia-related sleep disorders, and (sensitivity analyses) account for potential survival bias. Results: Overall, 25.5% of beneficiaries had OA at baseline (21.0% with OA and pain); 1149 elders (5.7%) were subsequently diagnosed with ADRD. Compared to beneficiaries without OA, those with OA were significantly more likely to receive a diagnosis of incident ADRD after adjustment for sociodemographics, lifestyle characteristics, comorbidities, and medications (adjusted odds ratio (AOR) = 1.23 (95% confidence interval (CI) 1.06, 1.42). Elders with OA and pain at baseline were significantly more likely to be diagnosed with incident ADRD than were those without OA or pain (AOR = 1.31, CI 1.08, 1.58). Sensitivity analyses yielded similar findings. Inclusion of depression/anxiety, but not sleep disorders, substantially attenuated these associations. Conclusion: Findings of this study suggest that: OA is associated with elevated ADRD risk, this association is particularly pronounced in those with OA and pain, and mood disorders may partially mediate this relationship. Show more

Keywords: Alzheimer’s disease and related dementias, arthritis, cognition, dementia, medicare current beneficiaries survey, mood, pain, sleep

DOI: 10.3233/JAD-191311

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 789-805, 2020